ABSTRACT - OVERALL Aging is an important risk factor for most common human diseases, including type 2 diabetes, cardiovascular disease, cancer and neurodegeneration. In the proposed collaborative U19 proposal, we will test a new approach for developing therapies for these diseases. Rather than focusing on individual diseases, we will explore genetic differences between successfully aged, healthy centenarians and control individuals with no family history of extreme longevity. Based on our own preliminary results, many of such genetic differences affect loci known to be involved in extreme longevity and health span in model organisms, such as worms and mice. Using the centenarian resource at the Albert Einstein College of Medicine, we will identify rare genetic variants and microRNAs associated with conserved mechanisms of healthy longevity as potential targets, for drug discovery (Project 1), evaluate these variants or associated pathways functionally in mouse models of aging, including natural aging, for phenotypes relevant for late-life human health (Project 2), and subsequently use them as leads for developing and testing small molecules targeting the pathways affected by these rare variants and miRNAs (Project 3). This integrated research project will be supported by two cores: an Administrative Core to coordinate the research (Core A) and a Genetically Engineered Mouse and Geropathology Core (Core B). Using our extensive genetic resources, including some from our pharmaceutical partner, Regeneron, we also will confirm further and validate some of the genetic variants and discover additional, novel genetic variants and associated pathways important for human longevity. The proposed project should greatly increase our understanding of the importance of the conserved pro-longevity pathways, identified and thus far mostly studied in model organisms, for human aging. Importantly, this gene to drugs collaborative project will be the first to use the genetics of rare individuals with healthy aging as a guide for the development of therapeutic approaches for targeting aging itself rather than its composite diseases for preventing, delaying onset and progression, and possibly even reverting many multiple age-related diseases.